Tamper resistant controlled release dosage forms

Abstract

In certain embodiments, the present invention is directed to a solid controlled release dosage form comprising: a core comprising a first portion of an opioid analgesic dispersed in a first matrix material; and a shell encasing the core and comprising a second portion of the opioid analgesic dispersed in a second matrix material; wherein the amount of opioid analgesic released from the dosage form is proportional within 20% to elapsed time from 8 to 24 hours, as measured by an in-vitro dissolution in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37 C.

What is claimed: 
     
       1. A solid controlled release dosage form comprising:
 hydrocodone or a pharmaceutically acceptable salt thereof dispersed in a matrix material comprising polyethylene oxide and a cellulose ether, wherein the dosage form is cured at a temperature of at least 60° C. for at least 1 minute; 
 wherein the amount of hydrocodone or pharmaceutically acceptable salt thereof released from the dosage form at 2 hours is less than about 25%, 
 at 4 hours is from about 10% to about 30%, 
 at 8 hours is from about 20% to about 60%, 
 at 12 hours is from about 40% to about 90%, and 
 at 18 hours is greater than about 70%; and 
 wherein the amount of hydrocodone or pharmaceutically acceptable salt thereof released from the dosage form is proportional within 20% at 8 and 24 hours, all as measured by an in-vitro dissolution in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37° C. 
 
     
     
       2. The solid controlled release dosage form of  claim 1 , wherein the polyethylene oxide has an average molecular weight from about 300,000 to about 10,000,000 as measured by correlation to viscosity. 
     
     
       3. The solid controlled release dosage form of  claim 1 , wherein the polyethylene oxide has an average molecular weight from about 1,000,000 to about 10,000,000 as measured by correlation to viscosity. 
     
     
       4. The solid controlled release dosage form of  claim 1 , wherein the cellulose ether comprises a hydroxyalkylcellulose. 
     
     
       5. The solid controlled release dosage form of  claim 4 , wherein the hydroxyalkylcellulose is hydroxypropylcellulose. 
     
     
       6. The solid controlled release dosage form of  claim 1 , wherein the matrix material further comprises microcrystalline cellulose. 
     
     
       7. The solid controlled release dosage form of  claim 6 , comprising a compressed dispersion of the hydrocodone or pharmaceutically acceptable salt thereof and the matrix material. 
     
     
       8. The solid controlled release dosage form of  claim 6 , comprising granules comprising the hydrocodone or pharmaceutically acceptable salt thereof and the matrix material. 
     
     
       9. The solid controlled release dosage form of  claim 8 , wherein the granules are compressed into a tablet. 
     
     
       10. The solid controlled release dosage form of  claim 6 , wherein the hydrocodone or pharmaceutically acceptable salt thereof is hydrocodone bitartrate. 
     
     
       11. The solid controlled release dosage form of  claim 10 , wherein the amount of hydrocodone bitartrate in the dosage form is from about 0.5 mg to about 1250 mg. 
     
     
       12. The solid controlled release dosage form of  claim 6 , which provides a C 24 /C max  ratio of hydrocodone of about 0.55 to about 1.0 after oral administration to a subject. 
     
     
       13. The solid controlled release dosage form of  claim 6 , which provides a T max  (h) of hydrocodone from about 4 to about 20 hours after oral administration to a subject. 
     
     
       14. The solid controlled release dosage form of  claim 12 , wherein the administration is a first administration to a population of subjects. 
     
     
       15. The solid controlled release dosage form of  claim 12 , wherein the administration is steady state administration to a subject. 
     
     
       16. The solid controlled release dosage form of  claim 6 , which contains about 20 mg hydrocodone or pharmaceutically acceptable salt thereof. 
     
     
       17. The solid controlled release dosage form of  claim 6 , which contains about 120 mg hydrocodone or pharmaceutically acceptable salt thereof. 
     
     
       18. The solid controlled release dosage form of  claim 6 , which provides a mean AUC (ng*h/mL) after oral administration to a subject of about 250 to 400 per each 20 mg hydrocodone or pharmaceutically acceptable salt thereof included in the dosage form. 
     
     
       19. The solid controlled release dosage form of  claim 6 , which provides a mean C max  (ng/mL) after oral administration to a subject of about 10 to about 30 per each 20 mg hydrocodone or pharmaceutically acceptable salt thereof included in the dosage form. 
     
     
       20. The solid controlled release dosage form of  claim 6 , which provides a mean T max  (h) after oral administration to a subject of about 10 to about 20. 
     
     
       21. The solid controlled release dosage form of  claim 6 , which provides a mean T 1/2  (h) after oral administration to a subject of about 5 to about 10. 
     
     
       22. The solid controlled release dosage form of  claim 6 , which provides a mean T lag  (h) after oral administration to a subject of about 0.01 to about 0.2. 
     
     
       23. The solid controlled release dosage form of  claim 6 , wherein the mean C 24 /C max  ratio is about 0.2 to about 0.8 after oral administration to a subject. 
     
     
       24. The solid controlled release dosage form of  claim 23 , wherein the administration is in the fasted state. 
     
     
       25. The solid controlled release dosage form of  claim 6 , wherein the mean AUC (ng*h/mL) after oral administration to a subject in the fed state is less than 20% higher than the AUC (ng*h/mL) after oral administration to a subject in the fasted state. 
     
     
       26. The solid controlled release dosage form of  claim 6 , wherein the mean C max  (ng/mL) after oral administration to a subject in the fed state is less than 80% higher than the C max  after oral administration to a subject in the fasted state. 
     
     
       27. The solid controlled release dosage form of  claim 6 , wherein the mean T max  (h) after oral administration to a subject in the fed state is within 25% of the T max  (h) after oral administration to a subject in the fasted state. 
     
     
       28. The solid controlled release dosage form of  claim 6 , wherein the mean T 1/2  (h) after oral administration to a subject in the fed state is within 8% of the T 1/2  after oral administration to a subject in the fasted state. 
     
     
       29. The solid controlled release dosage form of  claim 1 , comprising a core comprising a first portion of the hydrocodone or pharmaceutically acceptable salt thereof dispersed in a first portion of the matrix material; and a layer encasing the core and comprising a second portion of the hydrocodone or pharmaceutically acceptable salt thereof dispersed in a second portion of the matrix material. 
     
     
       30. The solid controlled release dosage form of  claim 29 , wherein the layer is a compression coating. 
     
     
       31. The solid controlled release dosage form of  claim 29 , further comprising a hydrophilic coating over the layer encasing the core. 
     
     
       32. The solid controlled release dosage form of  claim 31 , wherein the hydrophilic coating is a cosmetic coat. 
     
     
       33. The solid controlled release dosage form of  claim 29 , wherein the first portion of the matrix material comprises polyethylene oxide having an average molecular weight from about 300,000 to about 10,000,000 and the second portion of the matrix material comprises polyethylene oxide having an average molecular weight from about 300,000 to about 10,000,000, all as measured by correlation to viscosity. 
     
     
       34. The solid controlled release dosage form of  claim 29 , wherein the first portion of the matrix material comprises polyethylene oxide having an average molecular weight from about 300,000 to about 3,000,000 and the second portion of the matrix material comprises polyethylene oxide having an average molecular weight from about 4,000,000 to about 10,000,000, all as measured by correlation to viscosity.